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J. Biol. Chem., Vol. 283, Issue 21, 14391-14401, May 23, 2008

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Lansoprazole Protects and Heals Gastric Mucosa from Non-steroidal Anti-inflammatory Drug (NSAID)-induced Gastropathy by Inhibiting Mitochondrial as Well as Fas-mediated Death Pathways with Concurrent Induction of Mucosal Cell Renewal^*

Pallab Maity, Samik Bindu, Vinay Choubey, Athar Alam, Kalyan Mitra^¶, Manish Goyal, Sumanta Dey, Mithu Guha, Chinmay Pal, and Uday Bandyopadhyay¹

From the Department of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India and the Division of Drug Target Discovery and Development, ^¶Electron Microscopy Unit, Central Drug Research Institute, Chatter Manzil Palace, Mahatma Gandhi Marg, Lucknow-226001, Uttar Pradesh, India

We have investigated the mechanism of antiapoptotic and cell renewal effects of lansoprazole, a proton pump inhibitor, to protect and heal gastric mucosal injury in vivo induced by indomethacin, a non-steroidal anti-inflammatory drug (NSAID). Lansoprazole prevents indomethacin-induced gastric damage by blocking activation of mitochondrial and Fas pathways of apoptosis. Lansoprazole prevents indomethacin-induced up-regulation of proapoptotic Bax and Bak and down-regulation of antiapoptotic Bcl-2 and Bcl_xL to maintain the normal proapoptotic/antiapoptotic ratio and thereby arrests indomethacin-induced mitochondrial translocation of Bax and collapse of mitochondrial membrane potential followed by cytochrome c release and caspase-9 activation. Lansoprazole also inhibits indomethacin-induced Fas-mediated mucosal cell death by down-regulating Fas or FasL expression and inhibiting caspase-8 activation. Lansoprazole favors mucosal cell renewal simultaneously by stimulating gene expression of prosurvival proliferating cell nuclear antigen, survivin, epidermal growth factor, and basic fibroblast growth factor. The up-regulation of Flt-1 further indicates that lansoprazole activates vascular epidermal growth factor-mediated controlled angiogenesis to repair gastric mucosa. Lansoprazole also stimulates the healing of already formed ulcers induced by indomethacin. Time course study of healing indicates that it switches off the mitochondrial death pathway completely but not the Fas pathway. However, lansoprazole heals mucosal lesions almost completely after overcoming the persisting Fas pathway, probably by favoring the prosurvival genes expression. This study thus provides the detailed mechanism of antiapoptotic and prosurvival effects of lansoprazole for offering gastroprotection against indomethacin-induced gastropathy.

Received for publication, January 16, 2008 , and in revised form, March 25, 2008.

^* This work was supported by funds from Prof. Siddhartha Roy from the J. C. Bose National Award (to P. M.) and the Council of Scientific and Industrial Research (CSIR), New Delhi, through Suprainstitutional Project SIP 0007. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 91-33-24733491; Fax: 91-33-24730284; E-mail: ubandyo_1964{at}yahoo.com.

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This article has been cited by other articles:

				P. Maity, S. Bindu, S. Dey, M. Goyal, A. Alam, C. Pal, K. Mitra, and U. Bandyopadhyay Indomethacin, a Non-steroidal Anti-inflammatory Drug, Develops Gastropathy by Inducing Reactive Oxygen Species-mediated Mitochondrial Pathology and Associated Apoptosis in Gastric Mucosa: A NOVEL ROLE OF MITOCHONDRIAL ACONITASE OXIDATION J. Biol. Chem., January 30, 2009; 284(5): 3058 - 3068. [Abstract] [Full Text] [PDF]